Poster presentation

Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of catecholamines.
Expression of the tyrosine hydroxylase gene is regulated at the transcriptional level
by extracellular signaling molecules, including EGF, NGF, and glucocorticoids. We
have analyzed the stimulation of tyrosine hydroxylase gene transcription by the phorbol
ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in noradrenergic locus coeruleus-like
CATH.a cells and observed a striking enhancement of the transcriptional activation
potential of the ternary complex factor Elk-1, a key transcriptional regulator of
serum response element-driven gene transcription. Likewise, TPA strongly upregulated
the biosynthesis of the transcription factor Egr-1 via distal serum response elements
within the Egr-1 5'-flanking region. Subsequently, Egr-1 responsive transcriptional
activation was observed. Overexpression of Egr-1 was sufficient to activate transcription
of a tyrosine hydroxylase promoter/reporter gene, corroborating the view that the
tyrosine hydroxylase gene is a target gene of Egr-1. Expression of dominant-negative
mutants of Elk-1 or Egr-1 impaired TPA-induced stimulation of a tyrosine hydroxylase
promoter/reporter gene transcription. In contrast, dominant-negative mutants of the
transcription factors ATF2, ATF4, CREB, c-Jun and C/EBP did not change TPA-induced
tyrosine hydroxylase promoter activity, indicating that these proteins are not part
of the TPA-mediated signaling cascade directed towards the tyrosine hydroxylase gene.